Using Rh(III)-catalyzed C-H activation as a tool for the selective functionalization of ketone-containing molecules

Article abstract of DOI:10.1021/ol500258q

Due to the strong potential of C-H activation in many areas of organic chemistry, the use of a pre-existing carbonyl group for the installation of a directing group to enable selective and predictable α-alkenylation with activated olefins as coupling partners is described. This Heck-type reaction would then lead either to β,γ-unsaturated ketones or to variously substituted 1,4-butadienes depending on the conditions used for the cleavage of the directing group.

Full text of DOI:10.1021/ol500258q

Letter
pubs.acs.org/OrgLett
Using Rh(III)-Catalyzed C−H Activation as a Tool for the Selective
Functionalization of Ketone-Containing Molecules
Melissa Boultadakis-Arapinis, Matthew N. Hopkinson, and Frank Glorius*
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Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstrasse 40, 48149 Munster, Germany
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S
* Supporting Information
ABSTRACT: Due to the strong potential of C−H activation
in many areas of organic chemistry, the use of a pre-existing
carbonyl group for the installation of a directing group to
enable selective and predictable α-alkenylation with activated
olefins as coupling partners is described. This Heck-type
reaction would then lead either to β,γ-unsaturated ketones or
to variously substituted 1,4-butadienes depending on the
conditions used for the cleavage of the directing group.
etones are a very common motif in natural products and
biologically active compounds, including polyketides,
alkaloids, flavonoids, and steroids (Figure 1). The development
K
Figure 2. Rh(III)-catalyzed alkenylation of stabilized enolates.
Rh(III)-catalyzed alkenylation of enol-carbamates followed by
the derivatization of the obtained products and the application
of this methodology to natural products.
Figure 1. Structure of ketone-containing natural products.
As illustrated in Figure 2, the first step of the present work
was the installation of the directing group.8 Concerning the
subsequent functionalization step, the initial experiments were
performed with enol-carbamate 1a derived from acetophenone
and n-butyl acrylate (2a), in the presence of 2.5 mol %
[(Cp*RhCl2)2], 10.0 mol % AgSbF6, and 2.1 equiv of
Cu(OAc)2 as the catalytic system. The reaction optimization
indicated that protic solvents were best suited for this
transformation. Throughout this screening, MeOH gave the
best results leading to the formation of 3aa in 77% yield of the
two double-bond isomers (Z,E)-3aa and (Z,Z)-3aa in a ratio of
88:12 (Figure 3). On a larger 2.5 mmol scale, the yield and the
(Z,E)/(Z,Z) ratio improved to 95% and 92:8 respectively.
With the optimized conditions in hand, we examined the
scope of this transformation with both coupling partners
(Figures 3 and 4). Initially we studied the effect of the
substitution pattern of the aromatic ring with various
acetophenone-like enol-carbamates. The reaction proceeded
with electron-rich and -poor substrates with high efficiency,
leading to the desired conjugated dienes 3ba to 3ga with yields
of 62% to 85%, the (Z,E) diastereomer being the expected
major isomer in all cases. We were pleased to see that
naphthalene-substituted enol-carbamate 1h was suitable for this
transformation, giving diene 3ha in an excellent 95% yield.
of methods for the late-stage diversification of complex
molecules or for the synthesis of biologically active compounds
has attracted tremendous interest in the scientific community.
In this regard, the activation of C−H bonds has led to
significant advances in the field of organic chemistry over the
past 15 to 20 years.1 Based on all these facts, we focused our
interest on the use of pre-existing functional groups for the
selective and predictable functionalization of ketone-containing
molecules.
More specifically, a pre-existing enolizable ketone would
allow the installation of a directing group to perform selective
C−H activation. While the α-functionalization of ketones by
traditional methods (e.g., aldol chemistry or alkylation) is a well
explored fundamental aspect of synthetic chemistry,2 only
recently have metal-catalyzed transformations been extensively
developed.3 Despite great advances in the transition-metal-
mediated arylation of ketones, surprisingly little progress has
been made using other coupling partners.4 Over the past
decade, palladium-catalyzed decarboxylative transformations
such as allylations, propargylations, or allenylations of enolates
have been developed.5 However, the direct alkenylation of
enolates has been rarely exploited.6,7 We propose that by
trapping enolates with a suitable directing group, C−H
activation and functionalization of the vinylic position may be
achievable (Figure 2). More precisely, we report herein the
Received: January 23, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Letter
products 3ad and 3ae with the reduced products 3′ad and 3′ae
in 85% and 78% combined yield respectively. Methyl vinyl
sulfone (2f) underwent coupling with 1a to give the alkenylated
product 3af as a single isomer in 60% yield. Use of styrenes as
coupling partners was also feasible, albeit leading to moderate
to low yields due to partial conversion of the starting material
and difficult separation.
In order to validate the concept of the present work, the
scope of nonaromatic and/or cyclic enol-carbamates was also
investigated with n-butyl acrylate (2a) as the coupling partner
(Figure 5). The alkyl substituted enol-carbamates 4a, 4b, and
Figure 3. Variation of the aromatic ring of the enol-carbamate
moiety.a,b a Conditions: 1 (0.20−0.50 mmol), 2a (0.30−1.5 mmol),
2.5 mol % [(Cp*RhCl2)2], 10 mol % AgSbF6, 2.1 equiv of Cu(OAc)2,
solvent (0.2 M), 16 h, under Ar. b Isolated yields of a mixture of double
bond isomers (ratio of major (Z,E) isomer/minor isomers given in
c
brackets). At 100 °C.
Figure 5. Extension of the substrate scope to nonaromatic and/or
cyclic enol-carbamates.a,b a For conditions, see Figure 3. b Using 5.0
mol % [Cp*RhCl2]2, 20.0 mol % AgSbF6, in 1,4-dioxane at 100 °C.
4c were coupled with 2a under the standard conditions to give
the desired conjugated dienes 5aa, 5ba, and 5ca in 56%, 43%,
and 90% yield respectively. Interestingly, although these
conditions led to very poor conversion in the case of cyclic
enol-carbamates, the alkenylated products could be obtained
using our modified conditions. Thus, enol-carbamate 4d
derived from cyclohexanone gave the expected product 5da
in 46% yield. Coupling of enol-carbamates 4f and 4g, derived
from 1-indanone and camphor respectively, led to the
alkenylated products 5fa and 5ga in 48% and 70% yield
respectively. Finally, we were very pleased to establish that the
reaction was readily scalable, with compound 5ea being
obtained in a comparable 57% yield on a 10 mmol scale.
Aiming to develop a new method for the late-stage selective
functionalization of complex ketone-containing molecules, we
then focused our interest on the derivatization of these enol-
carbamates. First, it was important to show that the directing
group could be cleaved leading to the α-alkenylated ketone
(Scheme 1). However, this transformation proved particularly
challenging and could only be performed by use of the
Schwartz reagent.9 Thus, enol-carbamate 3ah was converted
into β,γ-unsaturated ketone 6 in 35% yield.
b
Figure 4. Variation of the olefin.a,b a For conditions, see Figure 3.
Isolated yields unless otherwise stated. c Using 5.0 mol %
[Cp*RhCl2]2, 20.0 mol % AgSbF6, in 1,4-dioxane at 100 °C. d NMR
yield using CH2Br2 as standard.
Moreoever, heteroaromatic rings were also well tolerated.
Indeed, 2-acetyl furan and 2-acetyl thiophene derived enol-
carbamates 1j and 1k promoted the formation of the desired
products 3ja and 3ka in excellent yields although 2-acetyl
pyridine derived substrate 1i led to an expected lowered yield,
presumably due to competitive complexation of the pyridine
nitrogen atom.
Subsequently, we investigated the scope of the second
coupling partner (Figure 4). The reaction of enol-carbamate 1a
with methyl acrylate (2b) afforded product 3ab in a very good
96% yield. Other activated olefins such as acrylonitrile, vinyl
ketones, and methyl vinyl sulfone were also compatible in the
reaction. The reaction with acrylonitrile (2c), performed in 1,4-
dioxane at 100 °C, provided a separable stereoisomeric mixture
of products 3ac (Z,E) and 3ac′ (Z,Z) in 73% combined yield.
Methyl vinyl ketone (2d) and ethyl vinyl ketone (2e) led to
high conversions as well, affording mixtures of the expected
Scheme 1. Cleavage of the Carbamate to the β,γ-Unsaturated
Ketone
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Inspired by the numerous reports on Ni-catalyzed C−O
bond cleavage of aryl carbamates from the groups of Garg,
Snieckus, and Shi,10 we then attempted similar transformations
on our system. As cyclic ketones are much more prevalent in
naturally occurring or biologically relevant compounds than
terminal methyl ketones, we decided to carry out this study on
the cyclic enol-carbamate 5ea (Figure 6). Surprisingly, the
reaction of 5ea in the presence of Cp2Zr(H)Cl led to the
quantitative formation of 7 after selective reduction of the ester
over the carbamate moiety.
deuterium after 16 h (see SI). For a better understanding, we
then studied the KIE of the reaction [eq 2]. Parallel
experiments were performed with 1a and D2-1a and a KIE of
5 was measured, suggesting that the C−H bond activation is
the rate-determining step.
Finally, in order to prove the concept described in the
present work, we decided to apply this methodology to
biologically relevant compounds (Scheme 3). Thus, the
reaction of flavanone derived enol-carbamate 11 and bis-
protected estrone 13 with n-butyl acrylate (2a) was
investigated.
Scheme 3. Application to Natural Products
Figure 6. Derivatization of the alkenylated enol-carbamates.
Moreover, reaction of 5ea with DDQ afforded the fully
aromatized product 8 in a very good 88% yield. We were very
pleased to see that the C−O bond of the carbamate moiety
could be cleaved under nickel catalysis in the presence of
arylboronic acids, giving the corresponding arylated products 9
and 9′. The same nickel catalyst was also used in combination
with TMDSO (tetramethyldisiloxane) leading in this case to
reduced compound 10 in 68% yield. A robustness screen was
also undertaken in order to investigate the applicability of this
method in the presence of several functional groups and
heterocycles (see Supporting Information (SI)).11
In the former case, the desired alkenylated product 12 was
obtained in a very good 71% yield in the conditions previously
optimized for cyclic enol-carbamates (Scheme 3A). In the case
of bis-protected estrone 13, this reaction afforded exclusively
the C16 monoalkenylated product 14 in 51% yield and no C2−
C16 bis-alkenylated product was observed. Alkenylation at the
C4 position was not envisaged due to steric reasons as
described in the literature (Scheme 3B).7b
In summary, we have developed the first example of a Rh-
catalyzed alkenylation of enolates. This transformation allows
the construction of linear 1,3-dienes from aryl, alkyl, and cyclic
enolates. The cleavage of the carbamate moiety then enables
the formation of either (E)-3-alkenones or various interesting
products by C−O bond activation under Ni catalysis. Finally,
the application of this methodology to natural products
demonstrates the potential of this strategy.
To gain insight into the mechanism of this transformation,
deuteration experiments and kinetic isotope effect (KIE)
studies were conducted (Scheme 2). When the reaction was
Scheme 2. Deuteration Experiments and KIE Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: glorius@uni-muenster.de.
Notes
performed in [D4]methanol in the absence of the olefinic
coupling partner, the incorporation of deuterium increased
from 10% after 30 min to 90% after 16 h [eq 1]. These results
may be attributed to the fact that either the C−H activation
process is slow or/and the intermediate rhodacycle is
thermodynamically stable in these conditions. Control experi-
ments were carried out in the absence of Cu(OAc)2 or
[(Cp*RhCl2)2], showing in both cases no incorporation of
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the European Research Council
under the European Community’s Seventh Framework
Program (FP7 2007-2013)/ERC Grant Agreement No.
25936 and by the Alexander von Humboldt Foundation
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Angew. Chem., Int. Ed. 2013, 52, 6033. For general reviews on the
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(8) Although the formation of enol-carbamates has often proved
challenging in this work, it should be noted that the unreacted ketone
could readily be recovered and retreated after the reaction in all cases.
Moreover, although we used a standard procedure for the installation
of the directing group, without any further optimization, other
protocols found in the literature seemed to be suitable for our
substrates (see ref 12). This was indeed recently demonstrated, as
enol-carbamate 4f derived from 1-indanone was formed in 82% yield
instead of the 40% obtained using the general procedure (see
Supporting Information).
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Collins (WWU) for his kind help.
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